A Study to Find Out Whether BI 1015550 Improves Lung Function in People With Idiopathic Pulmonary Fibrosis (IPF)

• BI 1015550 (Drug), also known as Nerandomilast, JASCAYD®: Participants received film-coated nerandomilast tablets orally twice daily at doses of either 9 mg or 18 mg, with each dose administered at least 12 hours apart and taken with 250 mL of water.
• Placebo (Drug): Participants received placebo matching 9 mg or 18 mg nerandomilast film-coated tablets orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.

Primary outcomes

• Absolute Change From Baseline in Forced Vital Capacity (FVC) [mL] at Week 52 [The MMRM model is a longitudinal analysis, and it incorporated FVC measurements from baseline (Week -8 to Week -1) and Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52]: The absolute change from baseline in Forced Vital Capacity (FVC) \[mL\] at Week 52 is reported. The absolute change from baseline in forced vital capacity (FVC) at Week 52 was analyzed using a restricted maximum likelihood (REML)-based mixed model with repeated measures (MMRM). The model included fixed categorical effects of treatment and baseline antifibrotic use at each visit, as well as the continuous effect of baseline FVC. Visit was treated as a repeated measure, with an unstructured covariance structure for within-patient variability.

Secondary outcomes

• Key Secondary Endpoint: Time to the First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute IPF Exacerbation, First Hospitalization for Respiratory Cause, or Death (Whichever Occurs First) Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: Time to the first occurrence of any component of the composite endpoint-acute IPF exacerbation, hospitalization for a respiratory cause, or death (whichever occurred first)-is reported as the number of participants who experienced one or more of these events during the trial. Acute IPF is defined as an acute, clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality, with all of the following: Acute worsening or development of dyspnea, typically of less than 1 month's duration. Computed tomography showing new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with IPF. Deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute IPF exacerbation, hospitalization, death.
• Time to First Acute IPF Exacerbation or Death Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: The time to first acute IPF exacerbation or death during the trial is reported as the number of participants who experienced either event. Acute IPF is defined as an acute, clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality, with all of the following: Acute worsening or development of dyspnea, typically of less than 1 month's duration. Computed tomography showing new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with IPF. Deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute IPF exacerbation followed by death.
• Time to Hospitalization for Respiratory Cause or Death Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: Time to hospitalization for respiratory cause or death over the duration of the trial is reported as the number of participants who experienced either event. Hospitalizations due to respiratory causes were recorded on a specific non-elective hospitalization CRF page. This page captured the hospitalization date, confirmation of a respiratory cause, and the primary admission diagnosis. If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: hospitalization for respiratory cause, followed by death.
• Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: The time to absolute decline of more than 10% from baseline in forced vital capacity (FVC) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy; Absolute decline in FVC % predicted of > 10% followed by death.
• Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: The time to absolute decline of more than 15% from baseline in diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. Predicted DLCO value was corrected for hemoglobin (Hb). If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: Absolute decline in DLCO % predicted of > 15%, followed by Death.
• Time to Death Over the Duration of the Trial [From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.]: Time to death over the duration of the trial is reported as the number of participants who died. Time to death will be based either on the date of death on the AE report for patients with AEs leading to death or will be based on the information from the vital status assessment.
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 [The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.]: The absolute change from baseline in the Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52 is reported. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline use of antifibrotic therapy, and baseline dyspnea score at each visit, with an unstructured covariance structure to model repeated measures. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment.
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 [The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.]: The absolute change from baseline in the L-PF Cough domain score at Week 52 is reported. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, and baseline L-PF Cough score at each visit, with an unstructured covariance matrix for repeated measures. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment.
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 [The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.]: The absolute change from baseline in the Living with Pulmonary Fibrosis (L-PF) Fatigue domain score at Week 52 is reported. The analysis used a mixed model for repeated measures (MMRM) with fixed categorical effects for treatment, baseline antifibrotic (AF) therapy, and the fixed continuous effect of baseline L-PF score. Covariance was unstructured. Baseline AF therapy was a covariate. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment.
• Absolute Change From Baseline in Forced Vital Capacity Percent Predicted at Week 52 [The MMRM model is a longitudinal analysis, and it incorporated FVC measurements from baseline (Week -8 to Week -1) and Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.]: The absolute change from baseline in Forced Vital Capacity percent predicted at Week 52 is reported. Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and the fixed continuous effects of baseline forced vital capacity (FVC) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate.
• Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide Percent Predicted at Week 52 [The MMRM model is a longitudinal analysis and it incorporated DLCO measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, and Week 52. The data represent the Least Squares Mean at Week 52.]: The absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted at Week 52 is reported. The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and the fixed continuous effects of baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate.

Sex: All, ages: 40 Years to any

Inclusion criteria

1. Patients ≥40 years old at the time of signed informed consent.
2. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial.
3. Diagnosis of Idiopathic Pulmonary Fibrosis (IPF).
4. Patients may be either:

   * on a stable therapy* with nintedanib or pirfenidone for at least 12 weeks prior to Visit 1 and during screening and are planning to stay on this background treatment after randomization. Combination of nintedanib plus pirfenidone is not allowed. (*stable therapy is defined as the individually and general tolerated regimen of either nintedanib or pirfenidone (no dose changes) for at least 12 weeks).
   * not on a treatment with nintedanib or pirfenidone for at least 8 weeks prior to Visit 1 and during the screening period (e.g. either Antifibrotic (AF)-treatment naïve or previously discontinued) and do not plan to start or re-start antifibrotic treatment.
5. Forced Vital Capacity (FVC) ≥45% of predicted normal at Visit 1.
6. Diffusing Capacity (of Lung) for Carbon Monoxide (DLCO) ≥25% of predicted normal corrected for hemoglobin (Hb) at Visit 1.
7. Women of childbearing potential (WOCBP) must be ready and able to use highly effective methods of birth control. WOCBP taking oral contraceptives (OCs) also have to use one barrier method.

Exclusion criteria

1. Prebronchodilator Forced Expiratory Volume in 1 second (FEV1)/Forced vital capacity (FVC) <0.7 at Visit 1.
2. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
3. Acute Idiopathic Pulmonary Fibrosis (IPF) exacerbation within 3 months prior to Visit 1 and/or during the screening period (investigator-determined).
4. Relevant chronic or acute infections including human immunodeficiency virus (HIV) and viral hepatitis.
5. Confirmed infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) not fully recovered according to investigator judgement within the 4 weeks prior to randomization (Visit 2).
6. Major surgery (major according to the investigator's assessment) performed within 6 weeks prior to Visit 2 or planned during the trial period, e.g. hip replacement. Registration on lung transplantation list would not be considered as planned major surgery.
7. Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1, except appropriately treated basal cell carcinoma of the skin, in situ squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
8. Aspartate aminotransferase (AST) or Alanine Aminotransferase (ALT) >2.5 x Upper limit of normal (ULN) or total Bilirubin >1.5 x ULN at Visit 1.

Further exclusion criteria apply.

Participant flow

Outcome results

• Absolute Change From Baseline in Forced Vital Capacity (FVC) [mL] at Week 52 (Primary), Least squares mean, Milliliters (mL): Placebo -183.48 (-210.86 to -156.10); Nerandomilast 9 mg BID -138.60 (-165.59 to -111.61); Nerandomilast 18 mg BID -114.65 (-141.81 to -87.50) (p 0.0222)
• Key Secondary Endpoint: Time to the First Occurrence of Any of the Components of the Composite Endpoint: Time to First Acute IPF Exacerbation, First Hospitalization for Respiratory Cause, or Death (Whichever Occurs First) Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 38; Nerandomilast 9 mg BID 32; Nerandomilast 18 mg BID 38 (p 0.5443)
• Time to First Acute IPF Exacerbation or Death Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 30; Nerandomilast 9 mg BID 31; Nerandomilast 18 mg BID 38 (p 0.5583)
• Time to Hospitalization for Respiratory Cause or Death Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 59; Nerandomilast 9 mg BID 57; Nerandomilast 18 mg BID 68 (p 0.9038)
• Time to Absolute Decline in Forced Vital Capacity (FVC) % Predicted of >10% From Baseline or Death Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 91; Nerandomilast 9 mg BID 89; Nerandomilast 18 mg BID 80 (p 0.7695)
• Time to Absolute Decline in Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) Percentage Predicted by More Than 15% From Baseline or Death, Measured Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 38; Nerandomilast 9 mg BID 35; Nerandomilast 18 mg BID 43 (p 0.9251)
• Time to Death Over the Duration of the Trial (Secondary), Count of participants, Participants: Placebo 28; Nerandomilast 9 mg BID 26; Nerandomilast 18 mg BID 21 (p 0.9084)
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 (Secondary), Least squares mean, Score on a scale: Placebo 7.26 (5.70 to 8.82); Nerandomilast 9 mg BID 6.26 (4.71 to 7.80); Nerandomilast 18 mg BID 6.63 (5.09 to 8.17) (p 0.3697)
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 (Secondary), Least squares mean, Score on a scale: Placebo 4.54 (2.49 to 6.59); Nerandomilast 9 mg BID 4.44 (2.42 to 6.46); Nerandomilast 18 mg BID 3.95 (1.93 to 5.97) (p 0.9442)
• Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Fatigue Domain Score at Week 52 (Secondary), Least squares mean, Score on a scale: Placebo 5.40 (3.66 to 7.14); Nerandomilast 9 mg BID 5.59 (3.88 to 7.30); Nerandomilast 18 mg BID 5.82 (4.11 to 7.54) (p 0.8759)
• Absolute Change From Baseline in Forced Vital Capacity Percent Predicted at Week 52 (Secondary), Least squares mean, FVC percent predicted: Placebo -4.92 (-5.67 to -4.18); Nerandomilast 9 mg BID -3.75 (-4.48 to -3.01); Nerandomilast 18 mg BID -3.19 (-3.93 to -2.45) (p 0.0280)
• Absolute Change From Baseline in Diffusing Capacity of the Lungs for Carbon Monoxide Percent Predicted at Week 52 (Secondary), Least squares mean, DLCO percent predicted: Placebo -6.14 (-7.35 to -4.94); Nerandomilast 9 mg BID -3.66 (-4.85 to -2.46); Nerandomilast 18 mg BID -4.47 (-5.66 to -3.27) (p 0.0042)

Adverse events

Time frame: AE collection and All-cause mortality From first trial drug administration (Placebo or Nerandomilast) up to 22.9 months.

Serious adverse events by term

299 more terms not shown.

Other adverse events by term

234 more sites not listed.

• Results publication: Wuyts WA, Richeldi L, Assassi S, Azuma A, Cottin V, Hoffmann-Vold AM, Kreuter M, Oldham JM, Martinez FJ, Valenzuela C, Wijsenbeek MS, Kanakapura M, James A, Weimann G, Drzewuski C, Coeck C, Maher TM. Design of an open-label extension trial of nerandomilast (BI 1015550) in patients with idiopathic pulmonary fibrosis and progressive pulmonary fibrosis (FIBRONEER-ON). BMC Pulm Med. 2025 Dec 4;26(1):10. doi: 10.1186/s12890-025-03973-7. PMID 41345848
• Results publication: Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, Oldham JM, Valenzuela C, Clerisme-Beaty E, Gordat M, Wachtlin D, Liu Y, Schlecker C, Stowasser S, Zoz DF, Wijsenbeek MS; FIBRONEER-IPF Trial Investigators. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2025 Jun 12;392(22):2193-2202. doi: 10.1056/NEJMoa2414108. Epub 2025 May 18. PMID 40387033
• Results publication: Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, Oldham JM, Valenzuela C, Gordat M, Liu Y, Stowasser S, Zoz DF, Wijsenbeek MS. Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF). BMJ Open Respir Res. 2023 Aug;10(1):e001563. doi: 10.1136/bmjresp-2022-001563. PMID 37597969

• Study Protocol (PDF, 2023-09-20)
• Statistical Analysis Plan (PDF, 2024-08-19)